CN117257805B - Application of nucleoside reverse transcriptase inhibitor in preparation of anti-vascular calcification drugs - Google Patents

Application of nucleoside reverse transcriptase inhibitor in preparation of anti-vascular calcification drugs Download PDF

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CN117257805B
CN117257805B CN202311497090.5A CN202311497090A CN117257805B CN 117257805 B CN117257805 B CN 117257805B CN 202311497090 A CN202311497090 A CN 202311497090A CN 117257805 B CN117257805 B CN 117257805B
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reverse transcriptase
nucleoside reverse
vascular calcification
pharmaceutically acceptable
calcification
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CN117257805A (en
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黄辉
马建帅
贺大雨
谢晨
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Eighth Affiliated Hospital of Sun Yat Sen University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Abstract

The invention discloses an application of nucleoside reverse transcriptase inhibitors in preparing medicaments for resisting vascular calcification; the nucleoside reverse transcriptase inhibitor is lamivudine or stavudine; the invention discovers that lamivudine or stavudine has the function of inhibiting vascular calcification and the progress thereof, and provides a new thought for the treatment of vascular calcification; and the lamivudine or stavudine has better drug safety and stronger vascular calcification resistance, is a known small molecular compound, can be dissolved in water or DMSO, has good stability and low cytotoxicity, and can be used as a candidate drug for vascular calcification resistance and related disease prevention and treatment.

Description

Application of nucleoside reverse transcriptase inhibitor in preparation of anti-vascular calcification drugs
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of nucleoside reverse transcriptase inhibitors in preparation of anti-vascular calcification medicines.
Background
Vascular calcification is a pathological phenomenon in which calcium phosphate is ectopic deposited in the vascular wall in the form of hydroxyapatite, similar to the bone formation process. Calcium and phosphorus deposits at different levels in blood vessels have different pathological manifestations, and vascular intimal calcification occurs in the areas of atherosclerosis lesions, whereas media calcification occurs mainly in aging, diabetes and end-stage renal disease. Vascular calcification has previously been considered a passive process and there is increasing evidence that vascular calcification is a highly regulated process similar to bone formation. Vascular calcification has complex generation mechanism, and oxidation stress reaction, inflammatory reaction, apoptosis, matrix vesicle generation, vascular injury, excessive calcium and phosphorus level, calcification inhibitor reduction, osteogenesis/cartilage induction factor stimulation, vascular smooth muscle cell phenotype transition and other factors can promote mineral deposition of extracellular matrix, so as to lead to vascular calcification.
The vascular calcification causes the increase of stiff vascular wall and the decrease of compliance, thereby causing myocardial ischemia, left ventricular hypertrophy and heart failure, promoting thrombosis and plaque rupture, being an important factor of high morbidity and high mortality of cardiovascular and cerebrovascular diseases, and seriously affecting the life quality and life span of people. Likewise, a study based on coronary calcification scores and the cumulative mortality of cardiovascular disease also suggests that vascular calcification is a critical risk factor for mortality of cardiovascular disease. However, current approaches to vascular calcification are quite limited. Therefore, the research on the pathogenesis of vascular calcification is deeply carried out, and the search of high-efficiency drugs for preventing or delaying the development of vascular calcification has important clinical significance.
Nucleotide reverse transcriptase inhibitors are approved drugs for the treatment of aids and hepatitis b infection, and have the effect of inhibiting the reverse transcription of viruses. However, it is not clear whether nucleotide reverse transcriptase inhibitors exert important regulatory effects in vascular calcification; therefore, the deep exploration of nucleotide reverse transcriptase inhibitors has great significance for regulating vascular calcification.
Disclosure of Invention
The invention aims to provide application of nucleoside reverse transcriptase inhibitors lamivudine and stavudine in preparation of anti-vascular calcification medicines.
The technical scheme adopted by the invention is as follows:
the invention provides an application of nucleoside reverse transcriptase inhibitors or pharmaceutically acceptable salts thereof in preparing medicaments for preventing and/or treating vascular calcification.
Preferably, the nucleoside reverse transcriptase inhibitor is lamivudine or stavudine.
Preferably, the nucleoside reverse transcriptase inhibitor or pharmaceutically acceptable salt thereof inhibits vascular smooth muscle cell calcification.
Preferably, the nucleoside reverse transcriptase inhibitor or a pharmaceutically acceptable salt thereof inhibits aortic calcification.
Preferably, the pharmaceutically acceptable salts include, but are not limited to: pharmaceutically acceptable acid addition salts, such as: salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and salts of organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid; salts of pharmaceutically acceptable bases are ammonium, alkali metal salts (e.g., sodium and potassium salts) and alkaline earth metal salts (e.g., magnesium and calcium salts), salts of tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine.
Preferably, the medicament contains an effective dose of a nucleoside reverse transcriptase inhibitor or a pharmaceutically acceptable salt thereof.
In the invention, the lamivudine or the pharmaceutically acceptable salt thereof obviously inhibits the cytogenesis and the vascular calcification at the concentration of 10-100 mu M; the stavudine or the pharmaceutically acceptable salt thereof significantly inhibits cytogenesis and vascular calcification at a concentration of 5-100 mu M.
Preferably, the lamivudine or a pharmaceutically acceptable salt thereof has a concentration of 20 to 50. Mu.M.
Preferably, the concentration of stavudine or a pharmaceutically acceptable salt thereof is 10 to 50 μm.
Preferably, the nucleoside reverse transcriptase inhibitor of the present invention or a pharmaceutically acceptable salt thereof is administered in a suitable daily dosage range of 0.001 to 100mg/kg body weight; the above-mentioned dosages may be administered in one dosage unit or in several dosage units, depending on the clinical experience of the physician and the dosage regimen involved in the application of other therapeutic means.
In the present invention, the lamivudine or a pharmaceutically acceptable salt thereof is administered to animals at a daily dose of 50 to 100mg/kg of mice and/or for a period of 8 to 15 days.
Preferably, the vascular calcification is atherosclerosis, aging, diabetes, chronic kidney disease, hypertension, vascular calcification accompanied or caused by vascular lesions.
Preferably, the medicament further comprises at least one other ingredient having a function of preventing and/or treating vascular calcification.
Preferably, the medicament further comprises pharmaceutically acceptable excipients.
Preferably, the pharmaceutically acceptable excipients include: at least one of a diluent, binder, wetting agent, lubricant, disintegrant, solvent, emulsifier, co-solvent, solubilizer, preservative, pH regulator, osmotic pressure regulator, surfactant, coating material, antioxidant, bacteriostat or buffer.
Preferably, the dosage form of the medicament comprises at least one of a suspension, a granule, a capsule, a powder, a tablet, an emulsion, a solution, a drop pill, an injection, an oral preparation, a suppository, an enema, an aerosol, a patch or a drop.
Preferably, the route of administration of the drug comprises at least one of intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, sublingual administration, nasal administration, nebulized administration or transdermal administration.
The beneficial effects of the invention are as follows:
the invention discovers that nucleoside reverse transcriptase inhibitors (lamivudine or stavudine) have the function of inhibiting vascular calcification and the progress thereof, and provides a new thought for the treatment of vascular calcification; and the lamivudine or stavudine has better drug safety and stronger vascular calcification resistance, is also known small molecular compounds, can be dissolved in water or DMSO, has good stability, can be used as candidate drugs for vascular calcification resistance and related disease prevention and treatment, and has good application prospect.
Drawings
FIG. 1 shows the results of alizarin red staining of vascular smooth muscle cells induced by high phosphorus at various concentrations of BCH-189.
FIG. 2 shows the results of calcium content measurements performed at various concentrations of BCH-189 on the high phosphorus-induced calcification of vascular smooth muscle cells.
FIG. 3 shows the results of alizarin red staining of vascular smooth muscle cells induced by high phosphorus at different concentrations of d 4T.
FIG. 4 is a graph showing the results of calcium content measurements performed at various concentrations of d4T on high phosphorus-induced vascular smooth muscle cell calcification.
FIG. 5 is a general alizarin red staining result of BCH-189 intervention on vascular calcification in vitamin D3 model mice.
FIG. 6 shows the results of Runx2 IHC staining of arterial rings of mice with BCH-189 intervention for vascular calcification in vitamin D3 model mice.
Where P <0.05, P <0.01, P <0.001, ns: no significant difference.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
Human vascular smooth muscle cell VSMCs were all purchased from saiorin biotechnology, inc; disodium hydrogen phosphate was purchased from the trade company, screening, sigma guangzhou; nucleoside reverse transcriptase inhibitors (lamivudine, stavudine all purchased from zicloud biotechnology Co., ltd., MCE, castor oil polyoxyethylene ether (cat No. C804845-250 ml), anhydrous glucose from Shanghai Michelin Biotechnology Co., ltd., calcium content kit from Nanjing's institute of biological engineering, vitamin D3 from biological engineering (Shanghai) Co., ltd., cat No. A600988-0001, alizarin red dye from Lei Gen, pengchen Biotechnology Co., ltd.;
the Lamivudine (Lamivudine, BCH-189) has the chemical formula shown in formula (I):
（I）；
stavudine (Stavudine, d 4T) has the formula (II):
（II）。
EXAMPLE 1 nucleoside reverse transcriptase inhibitor (BCH-189/d 4T) inhibiting vascular calcification
1. In this example, vascular smooth muscle cells were induced to undergo vascular calcification with phosphorus, and alizarin red staining was performed 7 days after intervention with nucleoside reverse transcriptase inhibitors (BCH-189), respectively, to evaluate the inhibitory effect of nucleoside reverse transcriptase inhibitors (BCH-189) on vascular calcification. The specific operation comprises the following steps:
1) 6-12 generation human vascular smooth muscle cells at 1 x 10 5 Well, 12-well plate was plated, and 1ml DMEM complete medium was added to each well. Calcification was induced by 3.0mM phosphorus at day1 after plating, with 1. Mu.M/5. Mu.M/10. Mu.M/25. Mu.M concentration of BCH-189, with replacement of DMEM complete medium every other day and 3.0mM phosphorus again, with 1. Mu.M/5. Mu.M/10. Mu.M/25. Mu.M concentration of BCH-189, and alizing with alizarin red staining at day 7.
2) 6-12 generation human vascular smooth muscle cells at 1 x 10 5 Well, 12-well plate was plated, and 1ml DMEM complete medium was added to each well. Calcification was induced by 3.0mM phosphorus at day1 after plating, with intervention at d4T at 1. Mu.M/5. Mu.M/10. Mu.M/25. Mu.M, replacement of DMEM complete medium at alternate days and re-administration of 3.0mM phosphorus, with intervention at d4T at 1. Mu.M/5. Mu.M/10. Mu.M/25. Mu.M, alizarin red staining at day 7.
2. To further elucidate the role of nucleoside reverse transcriptase inhibitors (BCH-189/d 4T) in inhibiting vascular calcification, phosphorus was used to induce vascular smooth muscle cells to undergo vascular calcification, and calcium assay was performed 7 days after intervention with nucleoside reverse transcriptase inhibitors (BCH-189/d 4T), respectively. The specific operation comprises the following steps:
1) 6-12 generation human vascular smooth muscle cells at 1 x 10 5 Well, 12-well plate was plated, and 1ml DMEM complete medium was added to each well. On day1 after plating, 3.0mM phosphorus was given to induce calcification while 1. Mu.M/5. Mu.M/10. Mu.M/25. Mu.M concentration of BCH-189 was given for intervention, DMEM complete medium was changed every other day and 3.0mM phosphorus was given again to induce calcification while 1. Mu.M/5. Mu.M/10. Mu.M/25. Mu.M concentration of BCH-189 was given for interventionThe calcium content was measured on day 7.
2) 6-12 generation human vascular smooth muscle cells at 1 x 10 5 Well, 12-well plate was plated, and 1ml DMEM complete medium was added to each well. Calcium was induced by 3.0mM phosphorus at day1 after plating, with intervention at d4T at 1. Mu.M/5. Mu.M/10. Mu.M/25. Mu.M, replacement of DMEM complete medium at alternate days and 3.0mM phosphorus again, with intervention at d4T at 1. Mu.M/5. Mu.M/10. Mu.M/25. Mu.M, and calcium assay at day 7.
Alizarin red staining results indicate that nucleoside reverse transcriptase inhibitors (BCH-189/d 4T) can significantly inhibit vascular calcification (FIGS. 1 and 3). Further calcium assay results also demonstrated that nucleoside reverse transcriptase inhibitors (BCH-189/d 4T) have vascular calcification inhibiting effect (FIGS. 2 and 4).
The result shows that the nucleoside reverse transcriptase inhibitor (BCH-189/d 4T) can effectively inhibit the occurrence of vascular calcification and can be used as an anti-vascular calcification medicament.
EXAMPLE 2 nucleoside reverse transcriptase inhibitor (BCH-189) inhibits vascular calcification in mice
1. In the embodiment, vitamin D3 is used for inducing vascular calcification of mice, wherein the vitamin D3 is vitamin D3 wrapped by castor oil polyoxyethylene ether; the preparation method comprises the following steps: (1) firstly, 200 mu L of absolute ethyl alcohol is used for dissolving 66mg of vitamin D3, and (2) 1.4mL of castor oil polyoxyethylene ether is added into the vitamin D3 ethanol solution to be uniformly mixed, and the mixture is kept stand at room temperature for 15min. (3) 750mg glucose powder was dissolved in 18.4mL sterilized ddH 2 O, preparing glucose aqueous solution, and standing at room temperature for 15min; (4) the two solutions were mixed and shaken well and stored at 4℃to give a VitD3 stock solution at a concentration of 132000 IU/mL. The whole process of preparing the liquid is kept sterile, and if the reagent cannot be guaranteed to be sterile, the liquid is filtered by a filter after being mixed. Animals were administered to induce vascular calcification in mice, and the mouse aorta was stained with alizarin red 10 days after intervention with a nucleoside reverse transcriptase inhibitor (BCH-189) to evaluate the inhibitory effect of the nucleoside reverse transcriptase inhibitor (BCH-189) on vascular calcification in mice.
The specific operation is as follows:
c57BL/6 male mice with similar body weights (20 g-25 g) at 8 weeks of age were randomly divided into a blank group (n=10), a vitamin D3 group (n=10), a vitamin D3+bch-189 group (n=10), and vitamin D3 model mice were intraperitoneally injected with vitamin D3 solution from Day1-3 at a dose of 500 IU/kg/Day, once daily at the same time; vitamin D3+ BCH-189 groups on the basis of administration of vitamin D3, intraperitoneal injection of BCH-189 mg/kg from Day1 was performed once daily, mice were sacrificed at Day10 and the mouse aorta was stained with alizarin red.
Alizarin red staining results showed that vitamin D3 successfully induced vascular calcification in mice, while nucleoside reverse transcriptase inhibitors (BCH-189) significantly inhibited the progression of vascular calcification in mice (fig. 5).
2. To further verify that nucleoside reverse transcriptase inhibitors (BCH-189) inhibited the development of vascular calcification in mice, vitamin D3 was used to induce vascular calcification in mice, and after 10 days of intervention with nucleoside reverse transcriptase inhibitors (BCH-189), the aortic rings of mice were individually subjected to Immunohistochemical (IHC) staining for the osteogenic phenotype Runx2 to further evaluate the inhibitory effect of nucleoside reverse transcriptase inhibitors (BCH-189) on vascular calcification in mice. The specific operation is as follows:
c57BL/6 male mice with similar body weights (20 g-25 g) at 8 weeks of age were randomly divided into a blank group (n=10), a vitamin D3 group (n=10), a vitamin D3+bch-189 group (n=10), and vitamin D3 model mice were intraperitoneally injected with vitamin D3 solution from Day1-3 at a dose of 500 IU/kg/Day, once daily at the same time; vitamin D3+ BCH-189 groups were given with vitamin D3, and from Day1, intraperitoneal injection of BCH-189 mg/kg was performed once daily, mice were sacrificed at Day10 and stained with mouse aortic annulus IHC, and the results showed that nucleoside reverse transcriptase inhibitors (BCH-189) significantly inhibited vascular calcification in mice (FIG. 6).
From the above results, it is found that the nucleoside reverse transcriptase inhibitor (BCH-189) can effectively inhibit vascular calcification of mice, and can be used as an anti-vascular calcification drug.
The present invention has been described in detail in the above embodiments, but the present invention is not limited to the above examples, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present invention. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.

Claims (8)

1. The use of nucleoside reverse transcriptase inhibitors or pharmaceutically acceptable salts thereof as sole active ingredient in the manufacture of a medicament for the treatment of vascular calcification; the nucleoside reverse transcriptase inhibitor is lamivudine or stavudine.
2. The use according to claim 1, wherein the nucleoside reverse transcriptase inhibitor or pharmaceutically acceptable salt thereof inhibits vascular smooth muscle cell calcification.
3. The use according to claim 1, wherein the nucleoside reverse transcriptase inhibitor or a pharmaceutically acceptable salt thereof inhibits aortic calcification.
4. The use according to claim 1, wherein the medicament comprises an effective dose of a nucleoside reverse transcriptase inhibitor or a pharmaceutically acceptable salt thereof.
5. The use according to any one of claims 1 to 4, wherein the medicament further comprises pharmaceutically acceptable excipients.
6. The use according to claim 5, wherein the pharmaceutically acceptable excipients comprise: at least one of a diluent, binder, wetting agent, lubricant, disintegrant, solvent, emulsifier, co-solvent, solubilizer, preservative, pH regulator, osmotic pressure regulator, surfactant, coating material, antioxidant, bacteriostat or buffer.
7. The use according to any one of claims 1 to 4, wherein the pharmaceutical dosage form comprises at least one of a suspension, a granule, a capsule, a powder, a tablet, an emulsion, a solution, a drop pill, an injection, a suppository, an enema, an aerosol, a patch or a drop.
8. The use according to any one of claims 1 to 4, wherein the route of administration of the medicament comprises at least one of intravenous injection, intraperitoneal injection, intramuscular injection, oral administration, sublingual administration, nasal administration, nebulized administration or transdermal administration.
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WO2011088126A2 (en) * 2010-01-13 2011-07-21 Eiger Biopharmaceuticals, Inc. Treatment of viral infection with prenyltransferase inhibitors
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